RANDOMISED CONTROL TRIAL OF I.V LEVETIRACETAM VS

RANDOMISED CONTROL TRIAL OF I.V LEVETIRACETAM VS.

FOSPHENYTOIN IN TERMS OF THEIR EFFECTIVENESS IN

STATUS EPILEPTICUS

Dissertation Submitted to

THE TAMILNADU DR. M.G.R. MEDICAL UNIVERSITY

In partial fulfillment of the regulations of

The award of the degree of

M.D IN PEDIATRIC MEDICINE

BRANCH VII

THANJAVUR MEDICAL COLLEGE,

THANJAVUR - 613 004.

THE TAMILNADU DR. M.G.R. MEDICAL UNIVERSITY

CHENNAI - 600 032.

MAY 2018

CERTIFICATE

I certify that the dissertation titled “RANDOMISED CONTROL

TRIAL OF I.V LEVETIRACETAM VS. FOSPHENYTOIN IN

TERMS OF THEIR EFFECTIVENESS IN STATUS EPILEPTICUS”,

submitted by Dr.KOWSIK.M, for the degree of DOCTOR OF

MEDICINE (PAEDIATRICS) (BRANCH VII), to The Tamil Nadu

Dr. M.G.R. Medical University, Chennai, is the result of original research

work undertaken by him in the Department of Paediatrics, Thanjavur

Medical College, Thanjavur.

Place: Thanjavur DEAN

Date: Thanjavur Medical College,

Thanjavur.

Prof Dr .S. RAJASEKAR. MD., DCH,

Professor and HOD of pediatrics,

Department of pediatrics,

Thanjavur medical college,

Thanjavur.

Dr. P. SELVAKUMAR MD.,

Associate professor of pediatrics,

Department of pediatrics,

Thanjavur Medical College,

Thanjavur.

CERTIFICATE – ІІ

This is to certify that this dissertation work titled “RANDOMISED

CONTROL TRIAL OF I.V LEVETIRACETAM VS.


STATUS EPILEPTICUS” of the candidate Dr.KOWSIK.M with

registration number 201517204 for the award of DOCTOR OF

MEDICINE in the branch of PEDIATRICS(Branch VII) .I personally

verified the urkund.com website for the purpose of plagiarism check. I

found that uploaded thesis file contains from introduction to conclusion

pages and result shows 2 percentage of plagiarism in the dissertation.

DECLARATION

I hereby solemnly declare that the dissertation titled “RANDOMISED

CONTROL TRIAL OF I.V LEVETIRACETAM VS.


STATUS EPILEPTICUS”, has been prepared by me under the guidance

of Dr.P.SELVAKUMAR. M.D., ASSOCIATE PROFESSOR,

DEPARTMENT OF PEDIATRICS THANJAVUR MEDICAL

COLLEGE, THANJAVUR. This is submitted to THE TAMILNADU

DR.M.G.R MEDICAL UNIVERSITY, CHENNAI, in partial fulfillment of

the requirement for the degree of DOCTOR OF MEDICINE

(PAEDIATRICS) (BRANCH VII).

Place: Thanjavur

Date: Signature

ACKNOWLEDGEMENT

I am extremely grateful to my guide DR.SELVAKUMAR.P, MD,

Associate Professor, Department of pediatrics, Thanjavur medical college, for

his scholarly guidance during my study and postgraduate period.

I gratefully acknowledge and express my sincere thanks to Prof.

Dr. JEYAKUMAR M.S, Mch, Dean, Thanjavur Medical College and

hospital, Thanjavur. for allowing me to do this dissertation and utilize the

institutional facilities.

I am extremely grateful to Prof. Dr. RAJASEKAR. MD., DCH.,

professor and HOD, Department of pediatrics Thanjavur medical college,

Thanjavur for his full-fledged support during my post graduate period.

I express my gratitude to my respected Co-guide, Assistant professor

Dr.C.S.SENTHIL KUMAR, MD., DCH, & Dr.N.ARAVIND

THIRUGNANASAMBANDHAM for their scholarly guidance and valuable

time they has rendered to do this work effectively.

I would also like to extend my warm gratitude to all the Assistant

Professors for their constant encouragement and support.

I would like to thank all my colleagues, juniors and friends who have

been a constant source of encouragement to me. Special thanks to all the

children and their parents who whole heartedly co-operated and participated in

this study.

Last but not the least, I would like to express my most sincere

gratitude to Dr.MUTHUKUMARAN, Dr.MAHESHWARAN, Dr.SHREE

JAYASUDHA, Dr.RAMESH PRASATH and Dr.ARUNEESHWAR for

their help and constant support for this thesis.

CONTENTS

S. No. Particulars PAGE No.

1. INTRODUCTION 1

2. REVIEW OF LITERATURE 2

3. AIMS AND OBJECTIVES 30

4. MATERIALS AND METHODS 31

5. ANALYSIS AND RESULTS 42

6. DISCUSSION 75

7. LIMITATION 79

8. SUMMARY 80

9. CONCLUSION 81

10. ANNEXURE 1

BIBLIOGRAPHY 82

11. ANNEXURE 2

PROFORMA 88

12. ANNEXURE 3

CONSENT FORM 95

13. ANNEXURE 4

ABBREVIATIONS 96

14. ANNEXURE 5

MASTER CHART 97

LIST OF TABLES

S.No. TABLES PAGE No.

1 Two operational dimensions in status epilepticus 3

2 Classification of seizure based on semiology 6

3 Classification of seizure based on etiology 7

4 Neurotransmitters in SE 8

5 Age of children in relation to prognosis of SE 13

6 Alteration of blood glucose in SE 13

7 Adverse effects of Levetiracetam 22

8 ‘P’ value and its significance 41

9 Comparison of case distribution based on age in

fosphenytoin and levetiracetam group 42

10 Comparison of case distribution based on gender in


11 Comparison of case distribution based on weight in


12 Comparison of case distribution based on developmental

status in fosphenytoin and levetiracetam group 48

13 Comparison of case distribution based on previous

seizure history in fosphenytoin and levetiracetam group 50

14 Comparison of case distribution based on previous AED

intake in fosphenytoin and levetiracetam group 52

15 Comparison of case distribution based on type of seizure

in fosphenytoin and levetiracetam group 54

16 Comparison of case distribution based on duration of

seizure in fosphenytoin and levetiracetam group 56

17 Comparison of baseline characteristics of the study

group and its ‘p’ value 59

18 Etiological profile of this study 60

19 Comparison of seizure cessation rate in fosphenytoin

and levetiracetam group 62

20

Comparison of time taken to terminate seizures

following drug administration in fosphenytoin and

levetiracetam group

64

21 Comparison of recurrence of seizures following drug

administration in fosphenytoin and levetiracetam group 65

22 Comparison of seizure free duration following drug


23

Comparison of length of PICU & Hospital stay

following drug administration in fosphenytoin and

levetiracetam group

68

24

Comparison of life threatening adverse events following

drug administration in fosphenytoin and levetiracetam

group

71

25 Comparison of specific adverse events following drug


26 Comparison of efficacy of FPHT and LEV 73

27 Mortality and its association in this study 74

28. Comparison of various studies with regarding to seizure

cessation rate. 76

LIST OF FIGURES

S.No. FIGURES PAGE No.

1 Pathophysiology of SE 9

2 Treatment protocol for pediatric SE 17

3 Chemical structure of LEV 19

4 Chemical structure of FPHT 23

5 Comparison of distribution of age between FPHT &

LEV group 43

6 Comparison of distribution of gender between FPHT &

LEV group 45

7 Comparison of distribution of weight between FPHT &

LEV group 47

8 Comparison of developmental status between FPHT &

LEV group 49

9 Comparison of previous seizure history between FPHT

& LEV group 51

10 Comparison of previous AED intake between FPHT &

LEV group 53

11 Comparison of type of seizure between FPHT & LEV

group 55

12 Comparison of duration of seizure between FPHT &

LEV group 57

13 Comparison of baseline characteristics between FPHT &

LEV group 58

14 Etiological profile of fosphenytoin group 61

15 Etiological profile of levetiracetam group 61

16 Comparison of seizure cessation rate between FPHT

&LEV group 63

17 Comparison of time needed to terminate seizure

between FPHT &LEV group 64

18 Comparison of recurrence of seizure between FPHT &

LEV group 66

19 Comparison of seizure free interval between FPHT &

LEV group 67

20 Comparison of length of PICU stay between FPHT &

LEV group 69

21 Comparison of length of hospital stay between FPHT &

LEV group 69

22 Comparison of ‘p’ values of all primary and secondary

outcomes between FPHT & LEV 70

1

INTRODUCTION

Status epilepticus is defined as a seizure lasting more than 30 minutes

or recurrent seizures for more than 30 minutes during which the patient does

not regain consciousness.[1]

Status Epilepticus is a common medical neurological emergency

associated with high morbidity; if not, associated with mortality [2]

As an initial treatment, potent gamma-butyric agonists such as

benzodiazepines will be administered to stop the child’s convulsions.

Lorazepam and Diazepam are commonly used as first line drugs. They are

short acting drugs which produce immediate effects. A long acting

anticonvulsant drug is necessary to prevent recurrent convulsions. Phenytoin

and Phenobarbitone were frequently used to treat status epilepticus in children.

After the development of fosphenytoin, it is recommended as a second line

therapy but both phenytoin and fosphenytoin can cause blood pressure

reduction and arrhythmias.

Levetiracetam is another antiepileptic effective against status

epilepticus, which is associated with lower incidence of adverse effects. [3]

The purpose of this study was to determine whether intravenous

Fosphenytoin or intravenous Levetiracetam is a better second line

anticonvulsant based on efficacy and safety for treatment of convulsive Status

Epilepticus in pediatric population.

2

REVIEW OF LITERATURE

DEFINITION OF SEIZURE :

A seizure is defined as transient occurrence of signs and symptoms due

to abnormal excessive synchronous neuronal activity in brain.[4]

STATUS EPILEPTICUS

CLASSICAL DEFINITION:

Status epilepticus is classically defined as “condition characterized by

an epileptic seizure that is sufficiently prolonged or repeated at sufficiently

brief interval so as to produce an enduring and unvarying epileptic

condition”.[5]

ILAE DEFINITION

Status epilepticus is a condition resulting either from failure of the

pathway responsible for termination of seizure or from the initiation , which

lead to prolonged seizure (after time point t1 ). It is a condition, which may

have long term consequences (after time point t2) including neuronal injury ,

alteration of neuronal network and neuronal injury , depending on duration

and type of seizure[6].

3

TABLE 1 - TWO OPERATIONAL DIMENSIONS IN STATUS

EPILEPTICUS [6]

(t1 - time point 1; t2 - time point 2)

INDIAN ACADEMY OF PEDIATRICS[1]

Status Epilepticus (SE): A seizure lasting more than 30 minutes or recurrent

seizures for more than 30 minutes during which the patient does not regain

consciousness.

Operational Definition*: Generalized, convulsive status epilepticus in adults

and older children (>5 years old) refers to >5 min of (i) continuous seizures or

(ii) two or more discrete seizures between which there is incomplete recovery

of consciousness.

S.No TIME

POINT

OPERATIONAL

DIMENSION

TIME IN

CONVULSIVE

SE

TIME IN

FOCAL SE

1

After t1

*Seizures should be

regarded as “ continuous

seizure activity”

*It indicates when

treatment should be

initiated

5 min 30 min

2

After t2

*It indicates when long

term consequences may

appear.

10 min >60 min

4

Refractory SE: Seizures persist despite the administration of two appropriate

anticonvulsants at acceptable doses, with a minimum duration of status of 60

minutes by history or on observation.

Super-Refractory SE: SE that continues 24 hours or more after the onset of

anesthesia, including those cases in which the status epilepticus recurs on the

reduction or withdrawal of anesthesia.

Operational definition is used for the purpose of initiating treatment.[1]

5

BURDEN

The annual incidence of status epilepticus ranges from 9.9-41 per

10000 / year with peaks in pediatric population and elderly[7]

The burden of disease, estimated using DALY, accounts for 1% of the

total burden of disease in the world. The annual economic burden of seizure

disorder in our country is 0.5% of GNP [8].

Incidence of status epilepticus is more in poor population. Its

prevalence is higher in rural (1.9%) compared with the urban

population(0.6%).[8] In children the etiology is usually acute central nervous

system infection .

According to an UK study, majority of cases of status epilepticus occur

in children who are previously neurologically normal. Around quarter of the

cases of status epilepticus are due to prolonged febrile seizures and 17% of

them are acutely symptomatic [9].

6

RISK FACTORS FOR REFRACTORINESS [10]:

• Non convulsive status epilepticus

• Hyperglycemia at presentation

• Low Glasgow coma scale

• Focal motor seizures at onset.

CLASSIFICATION

BASED ON SEMIOLOGY [6]

TABLE 2 – CLASSIFICATION OF SEIZURES BASED ON

SEMIOLOGY

MOTOR ACTIVITY DEGREE OF IMPAIRED

CONSIOUSNESS

A With prominent motor activity

A1 - Tonic clonic SE

A2 - Myoclonic SE

A3 - Focal motor SE

B Without prominent motor

activity

B1 - NCSE with coma

B2 - NCSE without coma

BASED ON EEG:

Various factors to be scored are location, name of pattern, morphology, time

related features, modulation and effect of intervention on EEG.[6]

7

BASED ON ETIOLOGY [6]:

TABLE 3 CLASSIFICATION OF SEIZURES BASED ON ETIOLOGY

1 Acutely symptomatic Seizures due to head injury,

hypoxemia, hypoglycemia, acute

infection, electrolyte imbalance, drug

withdrawal or intoxication

2 Remote symptomatic Seizures secondary to static illness

(remote cerebral insult in neonatal

period)

3 Progressive encephalopathy Status epilepticus in children with

progressive CNS disorder ( lipid

storage disease, mitochondrial

disorder, Rasmussen encephalitis )

4 Cryptogenic status epilepticus Without any identifiable etiology

FEBRILE STATUS EPILEPTICUS

• It is a separate entity.

• It is the most common type of SE in children.[4]

• Febrile illness is the only provocation for status epilepticus. It

should be considered after excluding direct CNS infection.

8

BASED ON AGE [6]:

• Neonatal (< 30 days)

• Infancy

• Childhood (2- 12 years)

• Adolescence

• Elderly (above 60 years)

•

PATHOPHYSIOLOGY :

TABLE 4 – NEUROTRANSMITTERS IN SE [4]

Sustained Seizures are due to reduced inhibition and increased excitation

based on neuro- chemical levels.

1 Excitatory neurotransmitter

Glutamate is the most common one and

NMDA (N-Methyl D Aspartate )

receptor is involved

2 Inhibitory neurotransmitter

GABA (Gamma Amino Butyric Acid) is

the common inhibitory neurotransmitter.

9

FIGURE 1 – PATHOPHYSIOLOGY OF STATUS EPILEPTICUS

Status epilepticus results in both neuronal necrosis and apoptosis. Apoptosis

occurs as a result of increase in pro-apoptotic factors( like apoptosis inducing

factor, BAX protein and ceramide) and intracellular calcium.[4]

PGE2 can raise glutamate release and lower potassium current which

eventually lead to increased excitability.[4]

Sustained seizures reduce GABA inhibition progressively. At receptor level

GABAnergic pathway fails and seizures become resistant to

pharmacotherapy[4]

10

OTHER MALADAPTIVE CHANGES:

• Depletion of inhibitory neuropeptides like galanin , somatostatins and

neuropeptide in hippocampus.[11]

• Reduction of chloride gradient across neuronal membrane[11]

• Increase in expression of substance P and tachykinins[11]

PHYSIOLOGICAL CHANGES IN STATUS EPILEPTICUS

Generalized convulsive status epilepticus

Catecholamine surge Vigorous muscle activity Marked acidosis

& Central sympathetic drive

Tachycardia Hyperthermia Both respiratory

Tachypnoea & metabolic component

Cardiac arrhythmia

Associated with poor Acidosis resolves with

neurologic outcome control of seizure

11

ETIOLOGY [4]:

� New onset epilepsy of any type

� Febrile convulsion (6 months – 5 years)

� Hypoxic ischemic encephalopathy

� Infections (CNS infections-Encephalitis, Meningitis)

� Head trauma

� Metabolic causes (Hypoglycemia, Hyponatremia,

Hypomagnesemia, Hypocalcemia)

� Neurodegenerative disorders

� Neurocutaneous syndrome

� Toxins(camphor, heavy metals, organophosphates)

� Medication changes �Non compliance (anti-epileptic

drugs) Inadequate dosage.

� Ischemic Stroke (Arterial or Venous)

� Inborn errors of metabolism – Storage disorders

� Intracranial hemorrhage

� Systemic conditions (Hypertensive or Renal or Hepatic

encephalopathy)

� Brain Tumors

Acute symptomatic status epilepticus is the most common category in

pediatric population.

12

PROGNOSIS:

Factors that affect prognosis in children with Status Epilepticus are,

1. Type of seizure

2. Duration of seizure

3. Etiology of seizure

4. Age of the child

Type of seizure:

Focal and NCSE are associated with refractory status

epilepticus[10]

Duration of seizure:

Prolonged seizures lead to hypoglycemia, hypercarbia, hypoxia and

marked acidosis which eventually leads to neuronal destruction[12]

Etiology of seizure:

According to Nelgian et al, mortality is low in children classified as

idiopathic and febrile Status Epilepticus [13]. Most death occurs in children

with acute symptomatic and remote symptomatic causes. [14]

13

Age of the child:

TABLE 5 – AGE OF CHILD IN RELATION TO PROGNOSIS OF SE [15]

S. No. Age Sequelae rate

1 <1 year 29%

2 1-3 years 11%

3 >3 years 6%

COMPLICATIONS OF STATUS EPILEPTICUS:

1. Hypoxemia

It occurs due to impaired ventilation, excessive tracheobronchial

secretion and increased oxygen consumption.

Severe hypoxia and acidosis leads to impaired myocardial

contractibility, reduced stroke volume and hypotension.

2. Acidosis (both respiratory and metabolic)

3.Glucose alterations

TABLE 6 – ALTERATION OF BLOOD GLUCOSE IN SE

During early phase of

status epilepticus

Massive Catecholamine release

&Sympathetic surge Hyperglycemia

Prolonged status

epilepticus

Increased metabolic demand

Hypoglycemia

14

4. Blood pressure disturbances

BP and Heart rate rise at early phase due to massive sympathetic surge

and catecholamine release, but prolonged seizures lead to decline in blood

Pressure.

5. Intra Cranial Pressure

Increase in intra cranial pressure further interferes with cerebral

oxygen and substrate supply. This results in cerebral edema.

Other factors that contribute to increased intra cranial pressure are

hypoxemia, hypercarbia and metabolic acidosis with compensatory

vasodilatation and increased blood flow to cerebrum[16]

6.Other effects

Hyperpyrexia [17]

Hyperkalemia (due to rhabdomyolysis)

Acute renal failure due to myoglobinuria and hypotension

Apnea [18]

Aspiration pneumonia

Neurogenic pulmonary edema [18]

15

7.Morbidity

Neurologic sequelae (Focal motor deficit [4], Intellectual deficit,

Behavioral disturbances Epilepsy)

8. Mortality (3% - 9%)

DIAGNOSIS :

1. History and clinical examination using systematically designed

proforma.

2. Investigations in child with status epilepticus [1]

First line investigation

Without previous seizure history

1. Random blood sugar

2. Serum sodium (especially < 6 months)

3. Calcium (if < 2 years)

With previous seizure history

1. AED level

If febrile

1. Complete blood count

Lumbar puncture

16

Refractory status epilepticus

1. Video EEG recording

Second line investigation

1. EEG

2. Neuro imaging (MRI is most sensitive)

Special tests

1. If history suggestive of metabolic disorder, consider metabolic and

genetic testing.

2. Workup for autoimmune encephalitis.

3. Urine toxicology. (if clinical suspicion)

17

TREATMENT PROTOCOL

FIGURE 2 – TREATMENT OF CONVULSIVE STATUS

EPILEPTICUS IN CHILDREN AND ADULTS

18

GENERAL MANAGEMENT OF ACUTE SEIZURES:

STABILISING THE CHILD

In the convulsing child, initial supportive, therapeutic and diagnostic measures

need to be conducted simultaneously. The goal of the therapy is to stop

clinical end electrical seizure activity by promptly giving appropriate drugs, in

adequate doses, with attention to the possibility of complicating apnea,

hypoventilation and other metabolic abnormalities.

When stabilizing the child, the main priority in management is preserving vital

function. That is, protecting the airway, maintaining breathing, supporting the

circulation, and correcting the metabolic derangements.

PHARMACOTHERAPY

1. BENZODIAZEPINES :

They are first line anticonvulsants for the treatment of SE in children.

In our study

Midazolam was the benzodiazepine of choice.

Advantages of Midazolam:

Increased water solubility

Shorter duration of action &

Better local tolerance when injected intravenously [19]

19

Route of administration :

• Buccal

• Intranasal

• Intravenous & Intramuscular.[19]

Dosage:

0.15 -0.2 mg/kg (max upto 5 mg) -- may repeat in 5-10 min[1]

2.LEVETIRACETAM

Chemical structure

It is the S-enantiomer of alpha-ethyl-2-oxo-1-pyrrolidine acetamide,

with a molecular weight of 170.21 and the chemical formula C8H14N2O2.[20]

FIGURE 3 – CHEMICAL STRUCTURE OF LEVETIRACETAM

20

Mechanism of action

The proposed mechanism of levetiracetam action related to its binding

to synaptic vesicle protein (SV2A) is a predominant isoform of the three

known SV2 proteins [20]

Binding of the levetiracetam to SVA2 results in synaptic release of

glutamate and GABA [20]

Pharmacokinetics:

Volume of distribution

0.5 to 0.7 liter per kg

Tmax :

2 - 46 months � 1.4 hr

4 - 12 years � 0.5 hr

Half-life :

2 – 46 months � 5.3 hrs

4 – 12 years � 4.9 hrs

Clearance :

2 – 46 months � 1.4 ml/min/kg

4 – 12 years � 1.12 ml/min/kg

Protein binding :

Protein binding of levetiracetam is insignifigant (<10 %).

21

Metabolism :

Levetiracetam biotransformation pathway is not cytochrome p450

dependent.

It has low potential for significant pharmacokinetic interaction

because it’s major metabolic pathway is hydrolysis and it undergoes negligible

oxidative metabolism in liver. Levetiracetam does not induce or inhibit drug

metabolizing enzymes[20]

Excretion :

Main route of excretion is by renal route either in administered form

(66%) or as carbolic acid metabolite (pharmacologically inactive form) as a

result of amide functional group hydrolysis.[20]

Dosage :

Intravenous Levetiracetam

Acceptable dose ranges from 20- 60 mg / kg can be used for

convulsive status epilepticus with transient side effects even at upper limits

of dose range.

Reconstitution fluids :

The suitable diluents are 0.9 % sodium chloride, 5 % dextrose &

Ringer lactate.

Rate of infusion :

Rate of infusion is 5 mg / kg/min [1]

22

Storage :

It is stored between 20 – 25° C.

Adverse effects :

According to Oluwaseun Egunsola [21], the most common

adverse event that warrants discontinuation were behavioral problems

(10.9%) and somnolence (8.7%).

TABLE 7 – ADVERSE EFFECTS OF LEVETIRACETAM.

S.NO ADVERSE EVENT PERCENTAGE

1. Behavioral problems

More frequent[22] 2 Fatigue

3 Irritability

4 Unsteadiness

5. Somnolence

6 Nervousness

Less frequent[22] 4 Anorexia

5 Anxiety

6 Rhinitis

7 Abnormal hepatic function

Rare 8 Dermatological problems

9 Bone marrow suppression

23

3. FOSPHENYTOIN

Fosphenytoin sodium is a phosphate ester, prodrug of

phenytoin[23]. It was developed as replacement for phenytoin sodium.

Chemistry :

Chemical formula : C16H15N2O6P

Molar mass : 362.274 g/mol

FIGURE 4 - CHEMICAL STRUCTURE OF FOSPHENYTOIN

Mechanism of action :

Fosphenytion stabilizes neuronal membrane thereby prevents

recurrent detonation of normal neuronal cells during depolarization shift

which occurs in epileptic patients and consists of synchronous and large

depolarization over which action potential is overlapped. This is brought by

24

prolonging the inactivated stage of voltage sensitive sodium channel which

governs the refractory period of neuron. This results in inhibition of high

frequency discharges with negligible effect on low frequency discharges

which allows sodium channels to recover even when their inactivation is

continued. This effect of fosphenytoin has been noted at therapeutic

concentration[23].

Other effects like inhibition of glutamate response, facilitation of

GABA response and reduction in calcium influx have been oted at toxic

concentration[23]

Pharmacokinetics

The conversion half life of fosphenytoin is nearly 15 minutes. The

mechanism of conversion has not been established but phosphatases play a

primary role. Each mole of fosphenytoin is converted to one mole of formate,

phenytoin and phosphate[24, 25]

Absorption :

Fosphenytoin has a half-life of 15 minutes following intra venous

infusion. Fosphenytoin is completely bioavailable follow intramuscular

administration but peak concentration occurs approximately after 30

minutes.[24,25]

25

Plasma fosphenytoin concentration following intramuscular

administration is more sustained but lower than those following intra venous

infusion because of the time required for fosphenytoin absorption from the

site of injection.[24,25]

Metabolism :

Bioavailability of various market preparation may differ. Hence it is

adviced to use single brand. It is 95% - 99% protein bound (especially

albumin). The percentage bound is lowered as total fosphenytoin

concentration increases which is aresult of the fact that binding to plasma

proteins is saturable. [23]

Fosphenytoin takes the place of phenytoin in protein binding sites.

Phenytoin is metabolized by glucuronide conjugation as well as by

hydroxylation involving 2C19 and CYP2C9 in liver[23,24,25]

Volume of distribution :

Volume of distribution of fosphenytoin rises with dose and rate.

Volume of distribution is 4.3 – 10 liters .

Excretion :

5% unchanged form is excreted in urine. [23]

26

Advantage of fosphenytoin over phenytoin :

Fosphenytoin is water soluble pro-drug of phenytoin that has been

introduced to overcome the difficulties in intravenous phenytoin

administration , which it has replaced for use in benzodiazepine-resistant

status epilepticus.

Its advantages over phenytoin include more rapid intravenous infusion

and lower potential for cardiac and local tissue toxicity. Fosphenytoin can be

infused with both glucose and saline, but phenytoin cannot be administered in

a drip of dextrose solution (because it results in precipitation)[23]

Loading dose :

Loading dose for pediatric status epilepticus is 15mg PE /kg to 20mg

PE/kg[1]. In the body fosphenytoin is rapidly changed to phenytoin sodium ;

it’s doses are expressed in PE (phenytoin equivalents) [24,25]

Because of risk of hypotension, fosphenytoin should not be infused at a

rate of more than 150 mg PE/min in children. Continuous monitoring of

respiratory function, electrocardiogram and BP is mandatory[23].

Rate of infusion :

Rate of infusion is 2 – 3 mg PE/kg/min [1]

Compatible fluid :

5% dextrose and 0.9 % sodium chloride.

Concentration required is 1.5 – 25 mg PE/ml [1]

27

Adverse effects :

Side effects of fosphenytoin are similar to phenytoin and includes

cardiac arrhythmias, hypotension, CNS adverse effects(ataxia ,dizziness,

somnolence, nystagmus, diplopia)[23]

Intra venous injections result in local vascular injury(damage to

intima). This eventually leads to thrombosis of vein. Hence edema and

discoloration of injected limb occurs. Extravasation of solution results in

tissue necrosis[23]

Fall in BP and cardiac arrhythmias occur only on intra venous

injections.

28

Kensuke Nakamura et al concluded that levetiracetam and

fosphenytoin are equally efficacious in preventing recurrent seizures after the

termination of SE by benzodiapezines. Further adverse events were lower and

tolerable in LEV group.[26]

Vincent Alvarez et al did a retrospective comparative study on

phenytoin, levetiracetam and valproate as a second line status epilepticus

treatment in adults. In this study, phenytoin failed to control SE in 41.4%

patients and LEV in 48.3%. (p value is statistically insignificant)[27]

Chakravarthi S et al studied the effectiveness of LEV and FPHT

in adults with regard to primary and secondary outcomes. In their study,

phenytoin achieved control of seizures in 68.2% compared to 59.1% in LEV

and both the groups showed comparable results with respect to recurrence of

seizures, the need of ventilator support and death. They concluded that LEV

may be an attractive and effective alternative to phenytoin. [28]

In the study by Manjari Tripathi et al, hypotension, respiratory

depression, need of intubation, ICU care were not observed when status

epilepticus was terminated with intravenous loading dose of levetiracetam.[29]

Jaclyn O Connor et al concluded in their study, Levetiracetam is as

safe and effective as phenytoin for the treatment of status epilepticus with

lower incidence of adverse events.[3]

In a study by Knake et al, levetiractam terminated seizure activity in

all patients and is not associated with any serious adverse events. [30]

29

Ted Lee et al did a retrospective study on use of LEV in management

of toxic seizures and concluded that LEV used as a second line antiepileptic

terminated drug induced seizures and prevented seizure recurrence without

obvious adverse effects. [31]

According to Zeid Yasiry et al, the efficacy of phenytoin (50.2%) was

found to be lower when compared to levetiracetam (68.5%) [32].

In a study by Bernherds R Ogutu et al on the pharmacokinetics and

clinical effects of phenytoin and FPHT in children with severefalciparum

malaria and SE, they found that i.v or i.m fosphenytoin offers a convinent

alternative to i.v phenytoin. [25]

According to Ilo E Leppik et al’s preclinical and clinical studies on

phenytoin prodrug, they found that both i.v and i.m administrations of

FPHT maintained stable levels of phenytoin. Both i.v and i.m FPHT were

well tolerated by the patients as evidenced by the absence of serious

adverse reactions. [33]

30

AIM AND OBJECTIVES

� To compare the efficacy of I.V Fosphenytoin with I.V

Levetiracetam in a pediatric population suffering from Status

Epilepticus.

� To compare the safety of Fosphenytoin with Levetiracetam in a

pediatric population treated for Status Epilepticus.

� To compare the incidence of recurrence between Fosphenytoin and

Levetiracetam in a pediatric population with Status Epilepticus.

� To compare the incidence of adverse reactions between

Fosphenytoin and Levetiracetam when used to treat Status

Epilepticus in a pediatric population.

31

MATERIALS AND METHODS

STUDY DESIGN:

Prospective randomized control trial

STUDY SETTING:

Govt. Rajah Mirasdar hospital.

STUDY PERIOD:

January 2017 – July 2017

STUDY POPULATION:

1 month – 12 years old children who presented to Pediatric Emergency

department at Govt. Rajah Mirasdar Hospital in a convulsing state.

INCLUSION CRITERIA:

Children in age group of 1 month -12 years in whom seizure persisted

after two doses of I.V Midazolam (0.15 mg/kg/dose).

32

EXCLUSION CRITERIA:

� Child in shock.

� Children who were previously on oral Phenytoin or oral

Levetiracetam for seizure medications.

� Pre-hospital treatment records were unavailable.

� Administration of injectable AEDs (BZD, phenytoin,

levetiracetam, sodium valproate) in the previous 24 hrs.

SAMPLING TECHNIQUE:

Simple random sampling

SAMPLE SIZE:

Sample size for our study was calculated using openepi.com , keeping

the type 1 error (α) as 0.95 , power (β) as 0.8 , ratio of sample as 1 and mean

difference (σ) as 0.5, the sample size required for each group is 25. Hence for

two groups the sample required was 50.

33

METHODOLOGY OF COLLECTING DATA:

A written consent obtained from parents / guardian during the time of

enrolment.

The study sample was divided into two groups. Children treated with

Fosphenytoin constitute Group I and those who received Levetiracetam

constitute Group II.

HISTORY :

• Current seizure activity : nature of onset , duration , any

secondary generalization and the postictal sensorium in case the

seizure has subsided.

• Presence or absence of fever, any viral prodrome, ear discharge,

neck pain, irritability or any other intercurrent illnesses.

• Any prior history of seizures if present, specify if on

medications, dosage and compliance.

• Features of raised intracranial tension like headache / vomiting /

posturing.

• Intoxication or toxic exposure.

• Other CNS abnormality (e.g. Ventricular-peritoneal shunt, prior

CNS infection)

34

• Birth history (e.g. anoxic encephalopathy)

• Developmental history ( by using Trivandrum developmental

scale where all the milestones falling to the left of the vertical

line should have been achieved by the child)

• Family history of seizures

EXAMINATION:

• Vital signs: temperature, heart rate, respiratory rate and the

blood pressure.

• Look for features of respiratory distress, poor peripheral

perfusion and the hydration status

• Note the type of seizure activity present.

• Assess for features of raised intracranial pressure.

• Also assess for possible etiology: features of meningitis,

septicemia, trauma , neurocutaneous stigmata, toxin ingestion

and any peculiar body odour.

35

LABORATORY STUDIES:

Obtain laboratory studies based on age and likely etiologies.

• Blood glucose level

• Electrolyte levels (sodium, potassium, calcium and if possible

magnesium)

• Arterial blood gas analysis

• Toxicology screen (if suggestive history available)

• Complete blood count

• Renal function test

• Liver function test

• Cerebrospinal fluid examination

• Neuroimaging and Electroencephalography

36

STUDY FLOW-ALGORITHM:

Airway, breathing, circulation

Put the child in lateral position to avoid aspiration

1st dose of I.V Midazolam 0.15mg/kg

Wait 5 mins if no response

2nd dose I.V Midazolam 0.15 mg/kg

Wait 5 mins No response

Randomization

GROUP A GROUP B

I.V Fosphenytoin 20mgPE/kg -10 mins I.V Levetiracetam 30mg/kg -6 mins

PRIMARY ASSESMENT � after 5 minutes

No response

Inj. Phenobarbital 20 mg/kg I.V loading dose at 1mg/kg/min

Inj. Midazolam infusion as per guidelines

37

Following drug administration, we compared both groups with the

following parameters.

Primary outcome

Efficacy:

a. Whether the episode of convulsive status epilepticus was

terminated with FPHT and LEV.

b. The need to use additional antiepileptic drugs to terminate the presenting

convulsions

c. Time taken from administration of drug in emergency department/PICU

to termination of convulsion.

Cessation of status:

Defined as cessation of status and improving mental status following

administration of drugs.

Five minutes following the administration of study medication, assessment

will be performed by the pediatric postgraduate.

The patient will be examined for the following:

1. Jerky movements

2. Increased tone

3. Level of consciousness

38

Continued seizure activity is defined as presence of either jerky

movements or increased tone. If seizure activity is present, then the next

anticonvulsant is to be infused as per the study protocol.

The time at which convulsive activity has ceased (as defined above) is

recorded.

Secondary outcome:

a. Whether convulsions recurred within 24 hours after termination of

seizures following administration of FPHT and LEV.

b. Seizure free duration in case of recurrence.

c. Length of stay in PICU and hospital

d. Occurrence of life threatening hypotension: within 60 minutes of

administration of drugs.

e. Need for intubation ( within 60 minutes following study drug infusion

f. Incidence of adverse effects

(Hypotension: measured as greater than 20%reduction from baseline

Respiratory depression: measured as greater than 20%reduction from baseline)

Children will be assessed daily while they remain in-patients to watch

out for adverse events.

39

DATA ANALYSIS

68 children between the age group of 1 month to 12 years who had

Status Epilepticus and presented to Pediatric Emergency department at Govt.

Rajah Mirasdar hospital, Thanjavur, during the study period as shown in the

figure below. Those who had Status Epilepticus that persisted after 2 bolus of

BZD I.V Midazolam (0.15 mg/kg/dose) were included in this study. Children

with shock; on oral Phenytoin and Levetiracetam medications; and who were

discharged against medical advice were excluded from the study.

68 babies

Included 50 Children Excluded

(18 Children)

Group 1 Group 2

Fosphenytoin Levetiracetam

(n=25) (n=25)

Outcome analysis and result

Excluded:

• Children with shock;

• On oral Phenytoin and

Levetiracetam

• Discharged against

medical advice

40

AVAILABILITY, STORAGE AND DILUTION:

• Available strength of Fosphenytoin is 75 mg PE/ ml (10 ml vial).

(750 mg equivalent to 500mg of Phenytoin sodium).

• Available strength of Levetiracetam is 100 mg/ml (5 ml vial).

• Available strength of Midazolam is 1 mg/ml (5 ml vial).

STORAGE:

• Levetiracetam: It is stored at 25oC (77oF).

• Fosphenytoin: It is stored under refrigeration at 2-8 oC. Product

has to be discarded if kept at room temperature for more than 48

hours, after reconstitution.

• Midazolam: It is stored below 25oC.

DILUTION:

Commonly used diluent in our study was 0.9% sodium chloride

solution for Midazolam, Levetiracetam and Fosphenytoin.

INFUSION:

Levetiracetam:

• Concentration: Required dosage + 100 ml compatible fluid.

• Rate of infusion: 5 mg/kg/min.

Fosphenytoin:

• Concentration: 1.5 – 25 mg PE/ml.

• Rate of infusion: 2 mg PE/kg/min.

41

STATISTICAL ANALYSIS:

Comparisons of various domains of both groups were analyzed using:

A. Mann-Whitney U test,

B. Fisher’s Exact test,

C. Unpaired ‘t’ test

Inference of ‘P’ value is tabulated below:

TABLE 8 – ‘P’ VALUE AND ITS SIGNIFICANCE

S.NO. ‘P’ VALUE INTERPRETATION

1 Less than or equal to 0.01 Highly significant

2 Less than or equal to 0.05 Significant

3 More than 0.05 Not Significant

42

RESULTS AND ANALYSIS

BASELINE CHARACTERISTICS OF BOTH STUDY GROUP:

1) COMPARISON OF AGE IN BOTH STUDY GROUP:

TABLE 9 - COMPARISON OF CASE DISTRIBUTION BASED ON

AGE IN FOSPHENYTOIN AND LEVETIRACETAM GROUP

S.

No. Parameter

Group I

(Fosphenytoin)

(n=25)

Group II

(Levetiracetam)

(n=25)

‘p’ value Statistical

Test

1

Age(in

years)

3.34 ± 3.6

2.28 ± 2.19

0.657(NS)

Mann-

Whitney

U test

Data are expressed as mean ± SD. P value less than 0.05 is considered

as significant and Mann Whitney U test was used to test the significance.

Mean age in Fosphenytoin group was 3.34 ± 3.6 years whereas in

Levetiracetam group, it was 2.28 ± 2.19 years which was not statistically

significant (‘p’= 0.657).

43

FIGURE 5 - COMPARISON OF CASE DISTRIBUTION BASED ON AGE

IN FOSPHENYTOIN AND LEVETIRACETAM GROUP

*Data are expressed as mean ± SD.

*The height of the bar in the vertical bar diagram represents the

mean.

*The error bar represents the standard deviation.

*The total number of sample in each group was 25.

Mean Age

FPHT 3.34

LEV 2.28

0

0.5

1

1.5

2

2.5

3

3.5

4

ag

e i

n y

ea

rs

44

2) COMPARISON OF DISTRIBUTION OF GENDER IN FPHT &

LEV GROUP:


GENDER IN FOSPHENYTOIN AND LEVETIRACETAM GROUP

S.

No.

Parameter

(sex)

Group I

(fosphenytoin)

(n=25)

Group II

(levetiracetam)

(n=25)

‘p’

value

Statistical

Test

1 Male 64%(16) 72%(18)

0.762

(NS)

Fisher’s

Exact test

2 Female 36%(9) 28%(7)

Data are expressed as percentages. ‘p’ value less than 0.05 is considered

as significant and Fisher’s Exact test was used to test the significance.

• 34 male children (68%) and 16 female children (32%) with Status

Epilepticus were enrolled in this study.

• Among the male children, 16 of them were included in

Fosphenytoin group and remaining in Levetiracetam group.

• Of the female children, 9 of them received Fosphenytoin and

remaining received Levetiracetam.

45

FIGURE 6 – COMPARISON OF CASE DISTRIBUTION BASED ON

GENDER IN FOSPHENYTOIN AND LEVETIRACETAM GROUP

*Data are expressed as absolute numbers.

*The Length of the bar in vertical bar diagram represents

number of subjects (n).

*The total number of sample in each group is 25.

Male Female

FPHT 64 36

LEV 72 28

0

10

20

30

40

50

60

70

80

Pe

rce

nta

ge

46

3) COMPARISON OF WEIGHT OF THE CHILDREN BETWEEN

TWO GROUPS:

TABLE 11.COMPARISON OF CASE DISTRIBUTION BASED ON

WEIGHT IN FOSPHENYTOIN AND LEVETIRACETAM GROUP

S.

No. Parameter

Group I

(Fosphenytoin)

(n=25)

Group II

(Levetiracetam)

(n=25)

‘P’

Value

Statistical

Test

1 Weight

(in kg) 11.86 ± 8.9 10.42 ± 5.9

0.95

(NS)

Mann-

Whitney

U test

Data are expressed as mean ±SD. ‘p’ value less than 0.05 is

considered as significant and Mann Whitney U test was used to test the

significance.

In this study mean weight of children enrolled in Fosphenytoin group

was 11.86 ± 8.9 kg whereas in Levetiracetam group it was 10.42 ± 5.90 kg

which was not statistically significant (‘p’=0.95)

47


WEIGHT IN FOSPHENYTOIN AND LEVETIRACETAM GROUP

*Data are expressed as mean ± SD.

*The height of the bar in the vertical bar diagram represents the

mean.

*The error bar represents the standard deviation.

Hence this study is a randomized control using age, gender and weight

specific matching.

Mean weight

FPHT 11.86

LEV 10.42

9.5

10

10.5

11

11.5

12

Kil

og

ram

s

48

4) COMPARISON OF DEVELOPMENTAL STATUS:


DEVELOPMENTAL STATUS IN FOSPHENYTOIN AND

LEVETIRACETAM GROUP

S.no Parameter

Development

Group I

(Fosphenytoin)

(n=25)

Group II

(Levetiracetam)

(n=25)

‘P’

Value

Statistical

Test

1 Abnormal 32%(8) 28%(7)

0.999

(NS)

Fisher’s

Exact test

2 Normal 68%(17) 72%(18)

Data are expressed as percentages. ’p’ value less than 0.05 is

considered as significant and Fisher’s Exact test was used to test the

significance.

Among the 50 children, 30% (15) of them were developmentally

abnormal.

Of whom, eight were treated with Fosphenytoin and seven with

Levetiracetam.

However ‘P’ value was found to be statistically insignificant (0.999).

49

FIGURE 8 COMPARISON OF CASE DISTRIBUTION BASED ON

DEVELOPMENTAL STATUS IN FOSPHENYTOIN AND

LEVETIRACETAM GROUP


*The Length of the bar in the vertical bar diagram represents


Abnormal developmental status normal developmental status

FOSPHENYTOIN 7 18

LEVETIRACETAM 8 17

0

2

4

6

8

10

12

14

16

18

20

nu

mb

er

of

case

s

50

5) COMPARISON OF PREVIOUS HISTORY OF SEIZURES:


PREVIOUS SEIZURE HISTORY IN FOSPHENYTOIN AND

LEVETIRACETAM GROUP

S.

No.

Parameter

(Previous

seizure)

Group I

(Fosphenytoin)

(n=25)

Group II

(Levetiracetam)

(n=25)

‘P’

Value

Statistical

Test

1 Yes 36%(9) 28%(7)

0.762

(NS)

Fisher’s

Exact test 2 No 64%(16) 72%(18)

Data are expressed as percentage. ‘p’ value less than 0.05 is


significance.

Among the 50 children, 16 children had a previous history of seizures.

Among those, 9 of them were treated with Fosphenytoin and 7 with

Levetiracetam. The ‘p’ value was not significant.

51


PREVIOUS SEIZURE HISTORY IN FOSPHENYTOIN AND

LEVETIRACETAM GROUP




Previous seizure history No Previous seizure history

fosphenytoin 9 16

levetiracetam 7 18

0

2

4

6

8

10

12

14

16

18

20

nu

mb

er

of

case

s

52

6) COMPARISON OF FREQUENCY OF PREVIOUS ANTI-

EPILEPTIC DRUG INTAKE IN BOTH GROUPS:


PREVIOUS AED INTAKE IN FOSPHENYTOIN AND

LEVETIRACETAM GROUP

S.

No. Previous Drug

Fosphenytoin

Group

(n=25)

Levetiracetam

Group

(n=25)

Total

1 Sodium valproate 4 5 9

2 Phenobarbitone 6 2 8

3 No drug 15 18 33

TOTAL 25 25 50

Data is expressed in percentage. ‘p’ value less than 0.05 is


significance.

Out of 50 children, 17 of them had previous anti-epileptic drug

intake. 10 of them received Fosphenytoin and the remaining 7 children were

treated with Levetiracetam (p=0.762 , not significant).

53

FIGURE 10 - COMPARISON OF CASE DISTRIBUTION BASED ON

PREVIOUS AED INTAKE IN FOSPHENYTOIN AND LEVETIRACETAM

GROUP

sodium valproate Phenobarbitone

LEV 5 2

FPHT 4 6

0

1

2

3

4

5

6

7

8

9

10

nu

mb

er

of

case

s

54

7) COMPARISON OF TYPE OF SEIZURES IN BOTH GROUPS:


THE TYPE OF SEIZURE IN FOSPHENYTOIN AND

LEVETIRACETAM GROUP

S.

No.

Parameter

(type of

seizure)

Group I

(Fosphenytoin)

(n=25)

Group II

(Levetiracetam)

(n=25)

‘P’

Value

Statistical

Test

1 Focal 4%(1) 4%(1) 0.999

(NS)

Fisher’s

Exact test 2 Generalised 96%(24) 96%(24)

Data is expressed in percentage. ‘p’ value less than 0.05 is


significance.

Among the 50 children, only 2 children had focal seizures and

remaining 48 children had generalized tonic clonic seizures which was not

statistically significant (‘p’=1.000).

55

FIGURE 11– COMPARISON OF CASE DISTRIBUTION BASED ON THE

TYPE OF SEIZURE IN FOSPHENYTOIN AND LEVETIRACETAM

GROUP




Focal GTCS

Fosphenytoin 1 24

Levetiracetam 1 24

0

5

10

15

20

25

30

nu

mb

er

of

case

s

56

8) COMPARISON OF DURATION OF SEIZURES IN BOTH

GROUPS:

TABLE 16 - COMPARISON OF CASE DISTRIBUTION BASED ON THE

DURATION OF SEIZURE IN FOSPHENYTOIN AND LEVETIRACETAM

GROUP

S.

No. Parameter

Group I

(Fosphenytoin)

Group II

(Levetiracetam)

‘P’

Value

Statistical

TesT

1

Duration of

seizure

(in minutes)

21.48 ± 4.28 22.12 ± 4.97

0.628

(NS)

Unpaired ‘t’

test

Data is expressed as Mean ± SD. ‘p’ value less than 0.05 is considered

as significant and Mann Whitney U test was used to test the significance.

The mean duration of seizure activity in fosphenytoin group was

21.48 ± 4.28 minutes whereas in levetiracetam group it was 22.12 ± 4.97

minutes which was not statistically significant (‘p’=0.628)

57

FIGURE 12 COMPARISON OF CASE DISTRIBUTION BASED ON THE

DURATION OF SEIZURE IN FOSPHENYTOIN AND LEVETIRACETAM

GROUP

Duration of seizure

FPHT 21.48

LEV 22.42

21

21.2

21.4

21.6

21.8

22

22.2

22.4

22.6

tim

e (

min

)

58

FIGURE 13 COMPARISON OF ALL BASELINE CHARACTERISTICS

BETWEEN BOTH STUDY GROUPS:

Male Female

Previous

seizure

disorder

Previous

AED

intake

Abnormal

developm

ent status

Focal

seizuresGTCS

Fosphenytoin 16 9 9 10 8 1 24

Levetiracetam 18 7 7 7 7 1 24

0

5

10

15

20

25

30

nu

mb

er

of

case

s

59

TABLE 17 - BASELINE CHARACTERISTICS AND THEIR ‘P’ VALUE

S.

N

o.

Parameter

FPHT

Group

(n=25)

LEV

Group

(n=25)

‘P’

Value Inference

1 AGE (mean ± SD) in years 3.34 ± 3.6

2.28 ±

2.19

0.657 Not

significant

2. GENDER

Male 16(64%) 18(72%)

0.762 Not

significant Female 9(36%) 7(28%)

3. WEIGHT (in kg)

11.86 ±

8.9

10.42 ±

5.9

0.95 Not

significant

4 PREVIOUS

SEIZURE

DISORDER

Yes 9(36%) 7(28%)

0.762 Not

significant No 16(64%) 18(72%)

5

TYPE OF

SEIZURE

Focal 1(4%) 1(4%)

0.999 Not

significant GTCS 24(96%) 24(96%)

6. DEVELOPMENT

Abnormal 8(32%) 7(28%)

0.999 Not

significant Normal 17(68%) 18(72%)

7.

DURATION OF SEIZURES

(minutes)

21.48 ±

4.28

22.12 ±

4.97

0.628 Not

significant

60

TABLE 18 - ETIOLOGICAL PROFILE OF THIS STUDY POPULATION

S.n

o ETIOLOGY FPHT (n=25) LEV (n=25)

1 Cryptogenic 7(28%) 5(20%)

2 Acute CNS infection 4(16%) 6(24%)

3 Febrile seizures 4(16%) 4(16%)

4 HIE Sequelae 3(12%) 4(16%)

5 Seizure disorder

(non-compliance) 3(12%) 1(4%)

6 Syndromic association 1(4%) 1(4%)

7 Hypoglycemia 1(4%) 1(4%)

8 Thulasi oil intoxication 1(4%) 0(0%)

9 Seizure disorder

(Breakthrough disorder ) 0(0%) 1(4%)

10 Sepsis 1(4%) 0(0%)

11 Camphor intoxication 0(0%) 1(4%)

12 Post meningo-encephalitic

sequelae 0(0%) 1(4%)

61

FIGURE 14 – ETIOLOGICAL PROFILE OF FOSPHENYTOIN GROUP

FIGURE 15 – ETIOLOGICAL PROFILE OF LEVETIRACETAM GROUP

LEVETIRACETAM

CNS infections

HIE sequlae

Febrile seizure

cryptogenic

Non compliance of AED

Hypoglycemia

Break through seizure

camphor ingestion

Syndromic

FOSPHENYTOIN

CNS infection

Sepsis

HIE sequlae

Febrile seizures

cryptogenic

Non compliance of AED

Hypoglycemia

Syndromic association

Thulasi oil ingestion

62

STATISTICAL ANALYSIS OF THE OUTCOME OF THE STUDY:

PRIMARY OUTCOME:

A. TERMINATION OF SEIZURE ACTIVITY AFTER DRUG

ADMINSTRATION

TABLE 19-COMPARISON OF SEIZURE CESSATION RATE

FOLLOWING DRUG ADMINISTRATION IN FPHT AND LEV

GROUP

S.

No.

Parameter

(Termination

of seizure)

Group I

(Fosphenytoin)

(n=25)

Group II

(Levetiracetam)

(n=25)

‘P’

Value

Statistical

Test

1 Yes 84% (21) 92%(23) 0.6671

(NS)

Fisher’s

Exact test 2 No 16%(4) 8%(2)

In our study, seizure cessation rate following fosphenytoin

administration was 84% whereas for levetiracetam it was 92%.

However ‘p’ value was found to be insignificant.

The percentage of children requiring additional anti-epileptic drugs to

terminate the presenting convulsions was 16% and 8% for fosphenytoin

and levetiracetam group respectively.

63

FIGURE 16-COMPARISON OF SEIZURE CESSATION RATE

FOLLOWING DRUG ADMINISTRATION IN FOSPHENYTOIN AND

LEVETIRACETAM GROUP

Seizure controlled Seizure not controlled

FPHT 21 4

LEV 23 2

0

5

10

15

20

25

No

of

case

s

64

B. TIME TAKEN TO TERMINATE SEIZURES:

TABLE 20– COMPARISON OF TIME TAKEN TO TERMINATE

SEIZURES FOLLOWING DRUG ADMINISTRATION IN FPHT

AND LEV GROUP

S.

NO. Parameter

Fosphenytoin

Group

Levetiracetam

Group

‘P’

Value

Statistical

Test

1 Time needed

to terminate

seizure

2.5 ± 1.4 min 3.3 ± 1.16 min 0.029* Unpaired

‘t’ test

In our study the mean time taken to terminate seizures was 2.5 ± 1.4 minutes

in Fosphenytoin group. For Levetiracetam it was about 3.3 ± 1.16 minutes.

The ‘P’ value was found to be statistically significant (0.029)

FIGURE 17-COMPARISON OF TIME TAKEN TO TERMINATE

SEIZURES FOLLOWING DRUG ADMINISTRATION IN

FOSPHENYTOIN AND LEVETIRACETAM GROUP

Time taken to terminate seizure

Fosphenytoin 2.5

Levetiracetam 3.3

0

0.5

1

1.5

2

2.5

3

3.5

tim

e (

min

)

65

SECONDARY OUTCOMES:

C.RECURRENCE OF SEIZURE:

TABLE 21-COMPARISON OF RECURRENCE OF SEIZURE IN

FPHT AND LEV GROUP

S.

No.

Parameter

(Recurrence)

Fosphenytoin

Group

(n=21)

Levetiracetam

Group

(n=23)

‘P’

Value

Statistical

Test

1 Yes 9.5%(2) 17.5%(4)

0.44

Fisher’s

Exact

Test

2 No 90.5%(19) 82.5%(19)

3 Total 21 23

In our study, Fosphenytoin group had a recurrence of 9.5% whereas

levetiracetam group had 17.5% recurrence. The ‘P’ value was found to be

insignificant. Hence both fosphenytoin and levetiracetam had no significant

variations in causing breakthrough seizures.

66

FIGURE 18-COMPARISON OF RECURRENCE OF SEIZURE IN

FPHT AND LEV GROUP.

Recurrence No recurrence

FOSPHENYTOIN 9.5 90.5

LEVETIRACETAM 17.5 82.5

0

10

20

30

40

50

60

70

80

90

100

pe

rce

nta

ge

67

D.SEIZURE FREE INTERVAL:

TABLE 22 - COMPARISON OF SEIZURE FREE DURATION

FOLLOWING DRUG ADMINISTRATION IN FPHT AND LEV

GROUP WHEN SEIZURE RECURS

S.

No. Parameter

Fosphenytoin

Group(n=2)

Levetiracetam

Group(n=4)

‘P’

Value

Statistical

test

1. Seizure free

interval

(hours)

1.6±1.1

3.8±6.3

0.8

Mann

Whitney U

test

In our study, there was no significant variation in seizure free duration

following drug administration between both groups

FIGURE 19 - COMPARISON OF SEIZURE FREE DURATION

FOLLOWING DRUG ADMINISTRATION IN FPHT AND LEV GROUP

WHEN SEIZURE RECURS

Seizure free interval

FOSPHENYTOIN 1.6

LEVETIRACETAM 3.83

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

tim

e (

hrs

)

68

E.IMPACT ON HOSPITAL STAY:

TABLE 23- COMPARISON OF LENGTH OF PICU AND HOSPITAL

STAY IN FPHT AND LEV GROUP

S.

No.

Duration of

stay

Fosphenytoin

Group

Levetiracetam

Group

‘P’

Value

Statistical

test

1 PICU(hours) 42.3 ± 65.1 44 ± 26.7 0.105 Mann

Whitney U

test 2 Hospital(days) 5.8 ± 4.9 6.3± 3.7 0.311

There was no difference in the length of PICU (42.3 hours vs. 44

hours) and hospital stay between two groups. The mean duration of hospital

stay for Fosphenytoin group was 6.41 days and for Levetiracetam group was

6.06 days.

69

FIGURE 20- COMPARISON OF LENGTH OF PICU STAY IN FPHT AND

LEV GROUP

FIGURE 21- COMPARISON OF LENGTH OF HOSPITAL STAY IN

FPHT AND LEV GROUP

PICU stay

FOSPHENYTOIN 42.3

LEVETIRACETAM 44

41

41.5

42

42.5

43

43.5

44

44.5

tim

e (

hrs

)

Hospital stay

FPHT 5.8

LEV 6.3

5.5

5.6

5.7

5.8

5.9

6

6.1

6.2

6.3

6.4

tim

e i

n h

ou

rs

70

FIGURE 22- COMPARISON OF ‘P’ VALUES OF BOTH PRIMARY AND

SECONDARY OUTCOMES BETWEEN FOSPHENYTOIN AND

LEVETIRACETAM GROUP

*Statistically significant.

Time

needed to

terminate

seizure*

Recurrence

of seizure

Seizure free

intervalPICU stay

Hospital

stay

termination

of seizure

following

drug

administrati

on

p value 0.029 0.44 0.8 0.105 0.311 0.6671

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

p v

alu

e

71

E. NEED FOR VENTILATORY ASSISTANCE AND LIFE

THREATENING HYPOTENSION:

TABLE 24 – COMPARISON OF LIFE THREATENING ADVERSE DRUG

REACTIONS IN FPHT AND LEV GROUP

S.no Adverse event

observed

FPHT

Group

LEV

Group

1 Hypotension treated

with inotropes

1(4%)

1(4%)

These adverse effects

were documented in

children who needed

additional AEDs to

terminate the presenting

seizures.

2

Respiratory

depression

(ventilator

assistance)

4(16%)

1(4%)

72

F.ADVERSE EFFECTS:

TABLE 25 – COMPARISON OF SPECIFIC ADVERSE DRUG

REACTIONS IN FPHT AND LEV GROUP WHO DID NOT REQUIRE

ADDITIONAL AEDS

S.

No.

ADVERSE EFFECT FOSPHENYTOIN LEVETIRACETAM

1

Respiratory depression

(non-intubated)

1(4%) 0(0%)

2 Ataxia 1(4%) 0(0%)

3

Behavioral changes

(irritable cry &

somnolence)

0(0%) 1(4%)

4 Thrombocytopenia 0(0%) 1(4%)

73

TABLE 26 - DEPICTS THE COMPARISON OF EFFICACY OF BOTH

DRUGS

S.

No. Parameter

Fospheytoin

Group

Levetiracetam

Group

‘P’

Value Inference

1

Seizure

termination

rate

84% 92% 0.6671 Not

significant

1.

Time taken to

terminate

seizures

(minutes)

2.5±1.4 3.3 ± 1.16 0.029* Significant

2. Recurrence

of seizures 9.5% 17.5% 0.44

Not

significant

3.

Seizure free

interval

(hours)

1.6 ± 1.1 3.8 ± 6.3 0.8 Not

significant

4. PICU stay

(hours) 42.3± 65.1 44 ± 26.7 0.105

Not

Significant

5. Hospital stay

(days) 5.8 ± 4.9 6.3± 3.7 0.311

Not

significant

6. Adverse

events 8% 8% - -

In our study Fosphenytoin terminated seizures in 84% of the children

whereas levetiracetam’s seizure cessation rate was 92%. Fosphenytoin

terminated seizure earlier than Levetiracetam (2.5 minutes vs. 3.3 minutes; P=

0.029*).

Comparison of efficacy of Fosphenytoin and Levetiracetam in different

domains including recurrence of seizures, seizure free duration and hospital

stay were not statistically significant.

74

On comparing the secondary outcome following treatment with either

fosphenytoin or levetiracetam; 2 cases had adverse drug reactions in each

group. One child had respiratory depression requiring nasal oxygen and other

developed transient ataxia following fosphenytoin infusion. In levetiracetam

group behavioral changes and thrombocytopenia were the adverse events

noted.

Case fatality rate was 8% in our study. All the children required

additional AED & the cause of death was mutifactorial

TABLE 27 – MORTALITY AND ITS ASSOCIATIONS IN THIS STUDY

S.no PREDICTORS NUMBER OF CASES

(n=4)

FPHT LEV TOTAL

(n=4)

1 Age less than 1 year 3 1 4

2 Need of additional AEDs to

terminate seizures 3 1 4

3

Acute symptomatic etiology 2 1 3

Remote symptomatic etiology 1 0 1

4

Focal seizures 0 1 1

Generalize Tonic clonic

seizures 3 0 3

75

DISCUSSION

The study was done during a period of 6 months from January -June

2017. There were a total of 68 children who presented with status epilepticus

during this time period of which, 50 children fulfilled the inclusion criteria.

Among those 50 children, 25 of them were treated with Fosphenytoin and the

remaining with Levetiracetam.

In this study, we compared fosphenytoin with levetiracetam in terms of

their effectiveness (both efficacy and adverse drug reactions) in

benzodiazepine resistant status epilepticus.

In the study Group I (Fosphenytoin group), 64% were male children.

The mean age was 3.34 years; with a mean weight of 11.86 kg and mean

seizure duration of 21.48 minutes. Previous AED intake was found in 10 cases

and delayed developmental milestones in 32%.

In the study Group II (Levetiracetam group), 72% were male children.

The mean age was 2.28 years; with a mean weight of 10.42 kg and mean

seizure duration of 22.12 minutes. Previous AED intake was found in 7 cases

and delayed developmental milestones in 28%.

The most common type of seizure was GTCS followed by focal

seizures in 8%. None had myoclonic seizures.

76

The etiology of seizures in the study group with decreasing order of

frequency based on clinical findings were acute symptomatic (acute CNS

infection, hypoglycemia and intoxication), remote symptomatic , cryptogenic

status epilepticus and febrile status epilepticus.

In our study, seizure cessation rate following fosphenytoin

administration was 84% whereas for levetiracetam it was 92%. In a previous

study done by Zeid Yasiry et al, the efficacy of levetiracetam was 68.5% and

phenytoin was 50.2%. [32] In their study, 798 cases of convulsive SE were

analyzed retrospectively. The study by Alvarez et al throws a contrary picture

with seizure cessation rate of 58.2% and 51.7% for phenytoin and

levetiracetam respectively, which was statistically insignificant as in our

study. [27] There is no previous data comparing fosphenytoin with

levetiracetam in children.

TABLE 28 - COMPARISON OF VARIOUS STUDIES WITH REGARDING

TO SEIZURE CESSATION RATE

S.

No. Study

Phenytoin

/Fosphenytoin Levetiracetam ‘P’ Value

1 Our study 84%

(fosphenytoin) 92%

Not

significant

2 Zeid Yasiry et al 50.2%

(phenytoin) 68.5% -

3 Alvarez et al 58.2%

(phenytoin) 51.7%

Not

significant

77

In our study fosphenytoin terminated seizures earlier than levetiracetam.

The mean time taken to terminate seizures was 2.5 ± 1.4 minutes in

fosphenytoin group. For levetiracetam it was about 3.3 ± 1.16 minutes.

According to Jaclyn O’Connor and her associates, time needed to terminate

seizures was similar (P= 0.085) in both study groups. [3] However their study

was done on adults.

In the fosphenytoin group, 9.5% (2/21) had recurrence, whereas the

levetiracetam group had 17.5% (4/23) recurrence which is similar to the

results of a study in adults done by Chakravarthy et al. [28] It is not

comparable to the study done by Jacyln O’ Connor and her colleagues, where

breakthrough seizures occurred less in LEV group (22%vs.38% p=0.014*.)[3]

In our study, there was no significant variation in seizure free duration

following drug administration between both groups. None of the studies

compared this parameter.

There was no difference between the two groups in length of PICU

(42.3 vs. 44; p= 0.105) and hospital Stay (5.8 days hrs vs. 6.3 days; p= 0.311).

This was similar to the study conducted by Jaclyn O’ Connor et al between

these two drugs on adults. [3]

In a systematic review by Egunsola O et al on the safety of

levetiracetam in pediatric population, it was found that behavioral problems

and somnolence to be the most prevalent adverse event to levetiracetam. [21]

78

In our study, behavioral changes were observed in 4% of cases in the form of

irritable cry.

According to Kinshuk Sahaya, out of 755 patients, 29 patients were

recognized with fall in platelet count while on levetiracetam prophylaxis. [34]

In our study, only one child (4%) was documented to have thrombocytopenia.

The cause of thrombocytopenia is uncertain in view of associated sepsis in that

child.

In a study by Jamerson et al, 8 out of 12 patients treated with phenytoin

experienced phlebitis but was noted on only one case with fosphenytoin (P <

0.05)[35]. In our study, no case of phlebitis was documented.

According to Leppik and his colleagues, serious cardiovascular and

respiratory adverse reactions were not observed during IV infusion of FPHT

[33]. In our study, hypotension was noted in two cases (1 each from FPHT &

LEV group), but they also needed additional AEDs (like phenobarbital or

midazolam) to terminate the seizures.

In Ramsay RE and Wilder BJ et al study, 67% of patient receiving

parenteral phenytoin experienced transient CNS side effects like nystagmus,

ataxia and dizziness but no patient developed intolerance to fosphenytoin. [36]

In our study, ataxia was noted in 1 child (4%) treated with fosphenytoin, who

recovered on switching to oral anti-epileptic drugs.

79

LIMITATIONS OF THIS STUDY

• The sample size of the study was small.

• The primary outcome does not include electroencephalography

confirmation of seizure termination.

• The cause of death was multifactorial.

80

SUMMARY

50 children aged between 1 month and 12 years presenting to pediatric

emergency department at Govt. Rajah Mirasdar hospital, Thanjavur from

January 2017 to June 2017 with status epilepticus that has failed to terminate

with two doses of midazolam were included in this study. Children in shock,

who were on oral phenytoin and levetiracetam medications and who were

treated with injectable antiepileptic drugs in previous 24 hours were excluded

from this study.

Participants were administered 30 mg PE/kg of intravenous fosphenytoin

over 10 min & 30 mg/kg of intravenous levetiracetam over 6 min. The primary

outcome of the study is the clinical cessation of seizure activity and the need

for additional AED to terminate seizures. Secondary outcomes includes a)

recurrence, b) serious adverse events & c) length of PICU and hospital stay.

Fosphenytoin achieved control of SE in 89% patients compared to

levetiracetam in 82% (p=0.6671). Fosphenytoin terminated seizure earlier than

Levetiracetam (2.54mins vs. 3.3 mins; P=0.029). There was no significant

difference between the two groups with respect to recurrence of seizures

within 24 hours (p=0.44), seizure free duration when seizure recurs (p=0.8)

and duration of PICU and hospital stay (p=0.105 & 0.311) .The adverse events

did not differ significantly between two groups.

81

CONCLUSION

Fosphenytoin terminated seizures earlier than levetiracetam.

Levetiracetam may be an effective alternative to fosphenytoin in management

of SE in children in view of comparable efficacy in terms of termination of

seizures, recurrence of seizures, adverse events & length of hospital stay.

82

ANNEXURE 1

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88

ANNEXURE 2

PROFORMA

NAME - AGE - SEX-

IP NO –

SOCIOECONOMIC STATUS: (modified Kuppusamy scale)

PRESENTING ILLNESS:

Seizure (duration, type, features)

H/O fever

H/O trauma

Other relevant history

PAST ILLNESS:

Whether a known case of seizure disorder or not?

Any AED intake –

TREATMENT HISTORY:

For the presenting complaints, whether the child had been treated outside with

any forms of injectable drugs.

FAMILY HISTORY:

Pedigree & Consanguinity:

ANTENATAL/ NATAL/POSTNATAL HISTORY:

(Relevant details)

89

IMMUNIZATION HISTORY:

DEVELOPMENTAL HISTORY

Gross motor/

Fine motor Cognition Social

Activities of

daily living

Delay in developmental

milestones

No delay in developmental

milestones

WEIGHT FOR AGE

Normal >80%

Grade I malnutrition 70 – 80%

Grade II malnutrition 60 – 70%

Grade III malnutrition 50 - 60%

Grade IV malnutrition < 50%

2.HEIGHT

90 %

90 -95%

85 -90%

< 85%

90

3. HEAD CIRCUMFERENCE

-3SD TO

-2SD

-2 SD

TO

-1 SD

-1SD

TO

MEDIAN

MEDIAN

TO

+1 SD

+ 1 SD

TO

+2 SD

+ 2 SD

TO

+3 SD

GENERAL EXAMINATION:

Look for dysmorphism&Look for neurocutaneous marker

VITALS: 1.HEART RATE:

Bradycardia

Normal

Tachycardia

(Using age specific Heart rate data)

2.RESPIRATORY RATE:

Bradypnoea

Normal

Tachypnoea

(Using age specific respiratory rate data)

3. BLOOD PRESSURE: (Expressed in centile)

Less than 5th centile

Normal

More than 95th centile

91

4.CAPILLARY REFILL TIME:

Normal

Prolonged

5.PERIPHERAL PULSES:

Not felt

Well felt

6.TEMPERATURE:

Febrile

Afebrile

SYSTEMIC EXAMINATION:

CNS

HIGHER MENTAL FUNCTION:

CRANIAL NERVES:

MOTOR: - Co-ordination

-BULK - TONE - POWER - REFLEXES

PLANTAR REFLEX:

INVOLUNTARY MOVEMENTS:

SENSORY:

92

CEREBELLAR

S/O MENINGEAL IRRITATION:

CVS

RS

ABDOMEN

DATA ANALYSIS

FOSPHENYTOIN LEVETIRACETAM

AVAILABILITY

COST


PREVIOUSLY

NEUROLOGIC

ALLY

NORMAL

PREVIOUSLY

NEUROLOGIC

ALLY

ABNORMAL

PREVIOUSLY

NEUROLOGIC

ALLY

NORMAL

PREVIOUSLY

NEUROLOGIC

ALLY

ABNORMAL

ANY PRE-

HOSPITAL

TREATMENT

WHETHER

STATUS

TERMINATED

TOTAL

DURATION

NEEDED TO

CONTROL

STATUS (from

drug

administered to

seizure activity

termination)

RECURRENCE

WITHIN 24 hrs

SEIZURE

93

FREE

INTERVAL

AFTER

INITIAL DOSE

(in case of

recurrence)

NEED OF

ADDITIONAL

AED

CESSATION OF STATUS :

It is the termination of all seizure activity within 30 minutes following drug

administration.

ABSENCE OF RECURRENCE :

It is absence of recurrence of seizure within 24 hours


INCIDENCE OF ADR

DURATION OF PICU

STAY

IMPACT IN HOSPITAL

STAY

FOSPHENYTOIN % observed LEVETIRACETAM % observed

Respiratory depression Somnolence

Hypotension Behaviour changes

Cardiac arrythmias ANY OTHERS

Extravastion of drug when

administered through IV

Did side effects warrant

discontinuation of therapy?

ANY OTHERS

94

INVESTIGATIONS:

CBC

RBS

SERUM ELECTROLYTES

SERUM CALCIUM

LFT

DIAGNOSIS:

Seizure type →

Etiology →

Syndromic association →

Etiology IV

Fosphenytoin

IV Levetiracetam

Non – compliance

Acute CNS infection

Febrile status

Metabolic cause

Miscellaneous

95

ANNXEURE 3

CONSENT FORM

I hereby give consent for my

child to participate in the study conducted by Dr.KOWSIK.M, post graduate

in Department of Pediatrics , Thanjavur Medical College , Thanjavur –

613001 and to use my child’s personal clinical data and result of investigation

for the purpose of analysis and to study the nature of disease.

Name of the participant-

Place –

Signature of Parent –

Date-

96

ANNEXURE 4

ABBREVIATIONS USED:

� AED – Anti-Epileptic Drug

� BP – Blood Pressure

� BZD – Benzodiazepines

� CNS – Central Nervous System

� HIE – Hypoxic Ischemic Encephalopathy

� PICU – Pediatric Intensive Care Unit

� LEV – Levetiracetam

� FPHT – Fosphenytoin

� SE– Status Epilepticus

� ILAE- International League Against Epilepsy

� PE- Phenytoin Equivalent

97

ANNEXURE 5

MASTER CHART

KEY TO MASTER CHART

S.No PARAMETER

Previous seizure

disorder

Y – Yes

N – No

2 Previous AED PBT – Phenobarbitone

SVP – Sodium valproate

3 Etiology SEP - Sepsis

SD - New onset seizure disorder

HIE - Hypoxic Ischemic Encephalopathy

FSE - Febrile Status Epilepticus

MEN Meningitis

SDNC – Seizure Disorder Non

Compliance of AED

ACI - Acute CNS infection

SDBS - Seizure Disorder

Breakthrough Seizures

SYN – Syndromic Association

HYPO - Hypoglycemia

4 Type of seizures F – Focal

G – Generalized tonic clonic

5 Developmental

History

AB – Abnormal

N – Normal

6 ADR(Adverse drug

reactions)

HT – Hypotension

RD – Respiratory depression

ATA – Ataxia

BC(IC) – Behavioral changes (Irritable cry)

THROM – Thrombocytopenia

DEA - Death

98

FP

S.No Name Age ( years) Yr to mth conv Age (month) Total in month age yr finalweight in

Kg

prev sez

disorder (Y/N)

AE drug

takenetiology

type of

seizure

duration

of seizure

(min)

develop

mental

history

time

drug adm

to sz

cessa

whether

seizure

terminat

ed or not

recurrenc

e

seizure

free

interval

(hrs)

need of

additiona

l drug to

terminat

e present

seizures

additiona

l AED to

terminat

e present

seizure

PICU stay

in hr

total

hospital

stay

(days)

ADR

documented

1

ADR

documen

ted 2

ADR

documen

ted 3

ADR

documen

ted 4

1 JAGADHEEP 0 0 6 6 0.5 4.5 Y PBT SEP F 26 AB 0 N Y PBT 288 17 HT(IN) RD(I)

2 KOWSALYA 9 108 108 9 18 N SD G 18 N 3 Y NR N 3

3 MOHAMMED AMEERA 0 11 11 0.916666667 8 Y PBT HIE G 31 N 1.5 Y NR N 3

4 KATHIR 3 36 4 40 3.333333333 12 N FSE G 28 N 2 Y NR N 8 7

5 VIBIN 0 8 8 0.666666667 5 N SVP HIE G 17 AB 0 N Y PBT+MID 84 3 RD(I) DEA

6 MEGHA 0 0 5 5 0.416666667 3.4 Y PBT MEN G 20 AB 0 N Y PBT+MID 18 0.75 RD(I) DEA

7 SATHRIYAN 0 6 6 0.5 5 N FSE G 21 N 3.5 Y NR N 5

8 HEMA SHREE 0 11 11 0.916666667 7 N SD G 16 N 3 Y NR N 24 3

9 SAI PRADAP 3 36 6 42 3.5 10 N SD G 22 N 2 Y NR N 3

10 NITHISH 3 36 36 3 11 N SD G 18 N 4 Y NR N 3.25

11 CHANDRU 3 36 36 3 12 N SD G 15 N 3.5 Y NR N 4 3

12 EZHILRANI 4 48 48 4 15 Y SVP SDNC G 23 AB 2 Y NR N 48 5

13 KAVISH RAJA 7 84 84 7 20 Y PBT SD G 26 N 1.5 Y NR N 20 3

14 THILSATH BEEVI 11 132 132 11 25 N SD G 15 N 2.5 Y NR N 7 3

15 VISHWA 3 36 36 3 10.2 N FSE G 24 N 3 Y NR N 24 4

16 KAVYA 1 12 1 13 1.083333333 7 N SYN G 18 AB 3 Y NR N 16 7

17 ANANYA 0 5 5 0.416666667 5 N ACI G 26 N 4 Y NR N 32 14

18 SHANKAR 11 132 132 11 31 Y SVP SDNC G 22 AB 3.5 Y R 2H 28M N 24 2

19 LITHESH 0 4 4 0.333333333 3 Y PBT ACI G 24 AB 0 N Y PBT+MID 23 1 RD(I) DEA

20 THILLAI RAJAN 1 12 12 1 8.5 N ACI G 18 N 3 y R 50M N 10 14 RD(NI)

21 THARIKA 0 0 1 1 0.083333333 3.3 N HG G 26 N 2.5 Y NR N 51 14

22 DINESH 1 12 6 18 1.5 7.5 Y PBT HIE G 22 AB 2 y NR N 3

23 YAMUNA 5 60 7 67 5.583333333 18.5 N FSE G 24 N 4 Y NR N 12 7

24 KARTHIKEYAN 1 12 3 15 1.25 8.5 N THULASI OIL G 18 N 5 Y NR N 104 16 ATA

25 SADASIVAMN 11 132 132 11 38 Y SVP SDNC G 19 N 4 Y NR N 7 2

LC LEVETIRACETAM

S.No Name Age ( years) Yr to mth conv Age (month) Total in month age yr finalweight in

Kg

prev sez

disorder (Y/N)

AE drug

takenetiology

type of

seizure

duration

of seizure

(min)

develop

mental

history

time

drug adm

to sz

cessa

whether

seizure

terminat

ed or not

recurrenc

e

seizure

free

interval

(hrs)

need of

additiona

l AED to

control

present

seizure

additiona

l AED to

terminat

e initial

seizure

PICU stay

in hr

total

hospital

stay

(days)

ADR

documented

1

ADR

documen

ted 2

ADR

documen

ted 3

ADR

documen

ted 4

1 RAMKUMAR 3 36 36 3 12.5 Y SVP PMS G 28 AB 4 Y NR N 25 4.5

2 JITHESH 2 24 6 30 2.5 11 N FSE G 16 N 3.5 Y R 13 H 22M N 72 10

3 ABISHEK 0 11 11 0.916666667 7 N SD G 17 N 4 Y NR N 3 BC(IC)

4 SIVAPRIYA 0 8 8 0.666666667 5.8 N ACI G 15 N 4.5 Y NR N 70 10

5 VINITH 1 12 6 18 1.5 9 N CRS G 26 AB 4 Y NR N 24 5

6 SAIKARTHIKEYAN 1 12 3 15 1.25 8 Y SVP HIE G 23 AB 3 Y NR N 3

7 MAHESH 1 12 1 13 1.083333333 10 N SD G 21 N 2.5 Y NR N 3

8 PREETHI 4 48 48 4 15 N ACI G 24 N 0 N Y PBT 98 14 RD(NI)

9 DHIVAN 2 24 24 2 11 N SD G 18 N 3.5 Y NR N 22 11

10 HARISH 0 7 7 0.583333333 5 N SD G 31 N 4 Y NR N 4

11 LOGANAYAKI 4 48 6 54 4.5 15 Y SVP SDNC G 28 AB 4.5 Y R 25 M N 48 7

12 HARISH 0 6 6 0.5 4.5 N HIE G 24 AB 3.5 Y NR N 4

13 KAVINESH 1 12 4 16 1.333333333 7.5 N FSE G 18 N 4 Y NR N 5

14 FAZIL 8 96 96 8 21 Y SVP SDBS G 17 N 3 Y NR N 2

15 KANISH 0 4 4 0.333333333 4 N ACI G 22 N 4 Y NR N 12 13 THROM

16 JEEVANSHREE 1 12 12 1 7 N CAMPHOR G 29 N 2 Y NR N 1

17 ROSHAN 1 12 6 18 1.5 10 N ACI G 20 N 3 Y NR N 28 10

18 YOGESHWARI 3 36 3 39 3.25 12 N SD G 16 N 4 Y NR N 3

19 MUTHUMANI 0 4 4 0.333333333 5 Y PBT HIE G 18 AB 4 Y R 1 H 30 M N 44 5

20 HARIVARSAN 6 72 6 78 6.5 30 N FSE G 31 N 4 Y NR N 10

21 SASIDHARAN 0 5 5 0.416666667 4.8 Y PBT HIE G 19 AB 3.5 Y NR N 5

22 ABDUL FAIZ 0 11 11 0.916666667 9 N ACI F 25 N 0 N Y PBT+MID 72 3 RD(I) HI(INO) DEA

23 ANBUSELVI 0 10 10 0.833333333 6.5 N FSE G 24 N 3 y NR N 15 10

24 EBSHIBA 7 84 84 7 18 Y SVP HYPO G 26 N 4 Y NR N 3

25 YAZHINI 3 36 3 39 3.25 12 N ACI G 17 N 3.5 Y R 18 M N 42 10

Documents

RANDOMISED CONTROL TRIAL OF I.V LEVETIRACETAM VS